The v-sis gene arose from an evolutionarily conserved, unique sequence cellular gene, designated c-sis. A structural analysis of human c-sis DNA clones has shown that regions corresponding to the v-sis coding sequence are arranged in five exons which stretch over approximately 12 kbp of the human genome. The nucleotide sequence of these exons has revealed that the human sis proto-oncogene is the structural gene for one of the two major polypeptides of PDGF. Using probes derived from sequences flanking the V-sis-related regions of human c-sis, it has been possible to identify an upstream exon of the c-sis transcriptional unit. This exon is not related to v-sis but is transcribed in certain human tumor cells. In attempts to assess the transforming potential of the normal c-sis human locus, it has been shown that transcriptional activation of a construct containing all of PDGF-2 coding exons as well as the upstream c-sis exon leads to the acquisition of high titered transforming activity. The cell-derived domain of Gardner-Rasheed feline sarcoma virus (GR-FeSV) consists of a Gamma-actin and a tyrosine-specific protein kinase coding sequence designated v-fgr. Utilizing a v-fgr probe it was possible to detect related sequences present at low copy number in DNAs of a variety of mammalian species and to isolate a human fgr homologue. Comparative studies revealed that this human DNA clone represented all but 200 base pairs of v-fgr. Analysis of human genomic DNA demonstrated that the fgr proto-oncogene was distinct from the cellular homologues of other retrovirus onc genes. In addition, the fgr proto-oncogene was localized to the distal portion of the short arm of human chromosome 1 at p36.1 by in situ hybridization. Taken together, our findings establish that the fgr proto-oncogene is a unique member of the tyrosine kinase gene family.